TWI469788B - 包含奧曲肽（ｏｃｔｒｅｏｔｉｄｅ）及二或多個聚乳酸交酯-乙交酯共聚物之持續釋放調配物 - Google Patents

包含奧曲肽（ｏｃｔｒｅｏｔｉｄｅ）及二或多個聚乳酸交酯-乙交酯共聚物之持續釋放調配物 Download PDF

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TWI469788B
TWI469788B TW95148218A TW95148218A TWI469788B TW I469788 B TWI469788 B TW I469788B TW 95148218 A TW95148218 A TW 95148218A TW 95148218 A TW95148218 A TW 95148218A TW I469788 B TWI469788 B TW I469788B
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microparticles
pharmaceutical composition
plgas
octreotide
polymer
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Holger Petersen
Markus Ahlheim
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Novartis Ag
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Description

包含奧曲肽(octreotide)及二或多個聚乳酸交酯－乙交酯共聚物之持續釋放調配物
本發明係關於一種持續釋放調配物，其包含作為活性成份之奧曲肽(octreotide)或其醫藥學上可接受之鹽及二或多個不同聚乳酸交酯－乙交酯共聚物(PLGA)。
指出根據本發明之該等醫藥組合物尤其用於指端肥大症患者之長期維持療法及治療與惡性類癌腫瘤及血管活性腸肽腫瘤(vasoactive intestinal peptide tumor)(vip瘤(vipoma tumor))相關之嚴重腹瀉及潮紅。
肽藥物通常經全身性投與，例如非經腸投與。然而，尤其對反覆每日投藥而言，非經腸投藥可為疼痛的且引起不適。為最小化對患者之注射次數，藥物應作為積存調配物來投與。使用可注射積存調配物之常見缺點為血漿含量之波動，諸如在整個釋放時期期間，高峰含量連同接近於0之血漿含量。
本發明揭示持續釋放調配物，其包含作為活性成份(藥物)之奧曲肽或其醫藥學上可接受之鹽。奧曲肽(US 4,395,403)為具有下式之生長抑素類似物：
活性成份可為呈醫藥學上可接受之鹽形式之奧曲肽，諸如與(例如)無機酸、聚合酸或有機酸之酸加成鹽，例如與鹽酸、乙酸、乳酸、檸檬酸、反丁烯二酸、丙二酸、順丁烯二酸、酒石酸、天冬胺酸、苯甲酸、丁二酸或雙羥萘酸(恩波酸(embonic acid))之酸加成鹽。例如視添加1當量或2當量酸而定，酸加成鹽可以單價鹽或二價鹽形式存在。較佳者為奧曲肽之雙羥萘酸單鹽。
藥物之粒度分佈影響藥物自積存形式之釋放概況。用以製備積存調配物之藥物為結晶或呈非晶形粉末形式。較佳者為非晶形粉末，其具有約0.1微米至約15微米(99%>0.1微米，99%<15微米)、較佳1微米至小於約10微米(90%>1微米，90%<10微米)之尺寸的粒子。藥物優先經歷微粉化製程以呈現所需粒度分佈。
本發明進一步提供持續釋放醫藥組合物(積存物)，其包含作為活性成份的奧曲肽或其醫藥學上可接受之鹽，該成份併入共聚(乳酸交酯－乙交酯)(PLGA)之摻合物或混合物中呈例如微粒、植入物或半固體調配物形式。
替代PLGA之摻合物，在本發明之另一態樣中，醫藥組合物包含含有活性成份之PLGA聚合物之混合物；亦即，活性成份可併入一或多種呈微粒、植入物或半固體調配物形式之PLGA中且隨後與亦包含活性成份及一或多種PLGA之另一微粒或植入物或半固體調配物混合。
根據本發明之醫藥組合物容許經大於3個月、優先為3個月與6個月之間的時期持續釋放活性成份。在釋放活性成份期間，奧曲肽之血漿含量係在治療範圍內。當然，奧曲肽之精確劑量將視包括欲治療之病狀、欲治療之病狀之嚴重性、個體之重量及療法持續時間之多種因素而定。
令人驚訝地，血漿含量之波動可藉由在根據本發明之醫藥組合物中使用二或多個不同PLGA之適合組合而顯著地減少。
藥物係併入由二或多個不同聚乳酸交酯－乙交酯共聚物(PLGA)組成之可生物降解之聚合物基質中。PLGA具有100：0至40：60、較佳90：10至40：60、更佳85：15至65：35之乳酸交酯：乙交酯單體比率。具有100：0之乳酸交酯：乙交酯單體比率(亦即不含有乙交酯單體)之PLGA為聚乳酸交酯(PLA)，其亦包括在根據本發明之PLGA之定義中。
根據本發明之PLGA具有在1,000至500,000 Da、較佳5,000至100,000 Da之範圍變化之分子量(Mw)。聚合物之架構可為具有上述建構嵌段之直鏈的、分枝的、超分枝的、梳狀分枝的、樹枝狀分枝、T形或星形聚合物。在本發明之一較佳實施例中，醫藥組合物中之至少兩種PLGA為直鏈的。
星形聚合物之實例為含有至少3個轉化成共聚(乳酸交酯－乙交酯)鏈之羥基之多元醇的酯。多元醇較佳為醣，最佳為葡萄糖。
根據本發明之PLGA之固有黏度(IV)在氯仿中低於0.9 dl/g，優先為在氯仿中低於0.8 dl/g。固有黏度可藉由如描述於(例如)"Pharmacopoe Europenne",1997，第17－18頁(毛細管管方法)中之流動時間量測之習知方法來量測。除非另外說明，否則該等黏度已在25℃下，在濃度為0.5%之氯仿中或在30℃下，在濃度為0.5%之六氟異丙醇(hexaisofluoropropanol)中量測。
根據本發明之PLGA之端基可為但不限於羥基、羧基、酯基或其類似基團。
積存調配物之藥物含量(負載量)係在1%至30%，較佳10%至25%，更佳15%至20%之範圍中。負載量定義為呈游離鹼之藥物與PLGA調配物之總質量之重量比。
適合聚合物為普遍已知的，但不限於以以下名稱市售之彼等聚合物：Boehringer Ingelheim Pharma GmbH & Co.KG,Ingelheim,Germany之RESOMER、Absorbable Polymers International(API)Pelham,AL,USA/DURECT Corp.,Cupertino,CA,USA之LACTEL、Alkermes,Inc.,Cambridge,MA,USA之MEDISORB、PURAC biochem BV,Gorinchem,The Netherlands之PURASORB。適合聚合物之實例列於表1中。
1)IV已在25℃下，在濃度為0.1%之氯仿中測定。2)IV已在30℃下，在濃度為0.5 g/dL之氯仿中測定。3)IV已在30℃下，在濃度為0.5 g/dL之六氟異丙醇中測定。
具有低可變性之血液含量可僅用根據本發明之醫藥組合物，而不用僅含有來自上文表中之一種單一聚合物之調配物，經大於3個月、優先為3個月與6個月之間的時間來達到。
另外，根據本發明之醫藥組合物可無菌地製造或可非無菌地製造且由γ輻射來最終滅菌。較佳為由γ輻射之最終滅菌，得到具有最高無菌性保證可能之產品。
根據本發明之醫藥組合物亦可含有一或多種0.1%至50%之量之調節釋放行為的醫藥賦形劑。該等藥劑之實例為：聚(乙烯吡咯啶酮)；羧甲基纖維素鈉(CMC－Na)；糊精；聚(乙二醇)；適合界面活性劑，諸如泊洛沙姆(poloxamer)(亦稱為聚(氧化乙烯－嵌段－環氧丙烷))、已知且以商標名TWEEN(例如Tween 20、Tween 40、Tween 60、Tween 80、Tween 65、Tween 85、Tween 21、Tween 61、Tween 81)市售之聚(氧化乙烯)－脫水山梨糖醇－脂肪酸酯、(例如)已知類型且以商標名SPAN市售之脫水山梨糖醇脂肪酸酯、卵磷脂、諸如碳酸鋅、氫氧化鎂、碳酸鎂之無機鹽或例如人類精蛋白或鮭精蛋白之精蛋白、或諸如聚離胺酸之承載胺殘基之天然或合成聚合物。
就組成、分子量及/或聚合物架構而言，根據本發明之醫藥組合物可為積存混合物或不同聚合物之聚合物摻合物。聚合物摻合物在本文中係定義為2或多個不同聚合物於一種植入物或微粒中之固體溶液或懸浮液。相反，積存物之混合物在本文中係定義為二或多個如具有不同組成之植入物或微粒或半固體調配物之積存物與一或多種於各積存物中之PLGA的混合物。較佳者為其中PLGA以聚合物摻合物形式存在之醫藥組合物。
根據本發明之醫藥組合物可呈植入物、半固體(凝膠)、一旦經注射即就地固化之液體溶液或懸浮液、或微粒形式。較佳者為微粒。包含奧曲肽或其醫藥學上可接受之鹽之微粒的製備為已知的且例如揭示於US 5,445,832或US 5,538,739中。
儘管說明書亦適用於植入物、半固體及液體，但是本發明之以下部分集中於聚合物微粒。
根據本發明之微粒可具有數亞微米至數毫米之直徑，例如約0.01微米至約2 mm，例如約0.1微米至約500微米之直徑。對醫藥微粒而言，直徑最多為約250微米，例如10至200微米，較佳10至130微米，更佳10至90微米。
根據本發明之微粒可(例如)在預填充注射器或小瓶中與抗聚結劑混合或由抗聚結劑塗佈或由抗聚結劑層覆蓋。適合之抗聚結劑包括(例如)甘露醇、葡萄糖、右旋糖、蔗糖、氯化鈉或(例如)具有上文所述之性質之諸如聚乙烯吡咯啶酮或聚乙二醇的水溶性聚合物。
對根據本發明之呈乾燥狀態之微粒而言，抗聚結劑較佳係以微粒之約0.1重量%至約10重量%，更佳為約3重量%至5重量%，例如約4重量%之量存在。在該態樣中之較佳抗聚結劑為甘露醇。
或者，抗聚結劑可在微粒之製造過程期間應用於該等微粒。舉例而言，在過濾/洗滌微粒之步驟，其可額外用抗聚結劑之水溶液來沖洗。因此，抗聚結劑層形成於微粒之表面上。較佳地，抗聚結劑係以小於微粒之10重量%，更佳小於微粒之2重量%，最佳小於微粒之0.5重量%之量存在於微粒中。在該態樣中之較佳抗聚結劑為甘露醇。
就微粒而言，更詳細地描述用於本發明之積存調配物之製造方法：微粒可藉由例如凝聚或相分離、噴霧乾燥、油包水(W/O)或水包之油包水(W/O/W)或水包之油包固體(S/O/W)乳液/懸浮液方法，接著溶劑萃取或溶劑蒸發之若干此項技術中已知之方法來製造。乳液/懸浮液方法為較佳方法，其包含以下步驟：(i)製備內部有機相，其包含(ia)溶解聚合物於適合之有機溶劑或溶劑混合物中；視需要溶解/分散適合之添加劑；(ib)溶解/懸浮/乳化藥物或藥物之水溶液於步驟(ia)中獲得之聚合物溶液中；(ii)製備含有穩定劑及視需要但較佳為緩衝鹽之外部水相；(iii)例如用產生高剪切力之裝置，例如用渦輪機或靜態混合器混合該內部有機相與該外部水相以形成乳液；及(iv)藉由溶劑蒸發或溶劑萃取固化微粒；(例如)用水洗滌微粒；視需要用例如甘露醇之抗聚結劑之水溶液沖洗微粒；收集且乾燥微粒，例如冷凍乾燥或真空乾燥，且將微粒篩過140 μm。
用於聚合物之適合有機溶劑包括(例如)乙酸乙酯、丙酮、THF、乙腈或例如二氯甲烷、氯仿之鹵代烴或六氟異丙醇。
用於步驟(iib)之穩定劑之適合實例包括0.1%至5%之量之聚(乙烯醇)(PVA)，0.01%至5%之總量之羥基乙基纖維素(HEC)及/或羥基丙基纖維素(HPC)、聚(乙烯吡咯啶酮)、較佳為豬明膠或魚明膠之明膠。
乾燥微粒組合物可(視需要)大批地或在填充於最終容器後藉由γ輻射(超殺滅菌(overkill sterilization))來最終滅菌，產生最高無菌性保證可能。或者，可將經大批滅菌之微粒再懸浮於適合媒劑中且作為懸浮液填充於諸如雙腔室注射器之適合裝置中，隨後冷凍乾燥。
根據本發明之含有微粒之醫藥組合物亦可含有媒劑以促進復水。
在投藥前，微粒係懸浮於注射用之適合媒劑中。較佳地，該媒劑為水基的，含有醫藥賦形劑，諸如甘露醇、氯化鈉、葡萄糖、右旋糖、蔗糖或甘油、非離子界面活性劑(例如泊洛沙姆、聚(氧化乙烯)－脫水山梨糖醇－脂肪酸酯)、羧甲基纖維素鈉(CMC－Na)、山梨糖醇、聚(乙烯吡咯啶酮)或單硬脂酸鋁以確保等張性且改善微粒之可濕性及沈積性質。濕潤劑及黏度增強劑可以0.01至2%之量存在；添加適合量之等張力劑以確保等張可注射懸浮液。
用於懸浮液之液體媒劑之量較佳為每劑量約1至5 ml，例如2至2.5 ml。若須要，呈乾燥形式之微粒及復水用之水性媒劑可分離地容納於雙腔室注射器中。
本發明進一步提供根據本發明之醫藥組合物尤其用於指端肥大症患者之長期維持療法及治療與惡性類癌及血管活性腸肽腫瘤(vip瘤)相關之嚴重腹瀉及潮紅的用途。
根據本發明之醫藥組合物之實用性可展示於標準臨床研究或動物研究中。
本發明進一步提供一種套組，其包含於視需要配備有一轉移組群之小瓶中的積存調配物，以及於安瓶、小瓶或預填充注射器中之水基媒劑或分離於雙腔室注射器中之微粒及媒劑。
 實例
以下實例為說明性的，但不用以限制本文中所述之本發明之範疇。實例僅意欲提出實踐本發明之方法。
實例1：微粒製備
將適當量之PLGA聚合物溶於適當量之二氯甲烷中以得到如表2中之"PLGA濃度"列所陳述之適當聚合物濃度。將適當量之藥物稱重於玻璃燒杯中且將聚合物溶液傾倒於藥物上以使所得微粒具有如"藥物負載量"列中所陳述之藥物負載量。
舉例而言，對具有20%之藥物負載量及20%之聚合物濃度之微粒而言，用量如下：將3.547 g之PLGA聚合物溶於17.7 ml二氯甲烷中以得到20%(w/v)聚合物溶液。將1.453 g之奧曲肽雙羥萘酸鹽(對應於1.00 g＝20%奧曲肽游離鹼)稱重於玻璃燒杯中且將聚合物溶液傾倒於藥物上。
在用冰/水混合物冷卻下，用Ultra－Turrax定子轉子混合器，以20'000 rpm將懸浮液均質化1 min。該懸浮液稱為S/O懸浮液。
將10.00 g聚乙烯醇PVA 18－88、3.62 g KH2 PO4 及15.14 g Na2 HPO4 溶於2.00 L去離子水中以形成緩衝至pH 7.4之0.5% PVA 18－88溶液。
藉由在可撓性管泵(Perpex，Viton管)之幫助下，以10 ml/min之速率抽吸S/O懸浮液至渦輪機中且藉由用齒輪泵(具有抽吸頭P140之Ismatec MV－Z/B)，以200 ml/min之速率抽吸水溶液至同一渦輪機中來使S/O懸浮液與0.5% PVA18－88溶液混合。在4'500 rpm下，將兩種溶液混合於渦輪機中。將均質化S/O/W乳液收集於經200 ml之緩衝PVA溶液預填充之2 L玻璃燒杯中。
隨後在3.5 h－5 h內，將S/O/W乳液加熱至52℃。將52℃之溫度另外保持30 min－120 min，之後將該批料再冷卻至室溫。在該過程期間，藉由真空移除逸出之二氯甲烷且藉由4葉片－螺旋漿式－攪拌器在250 rpm下將該批料攪拌。
結果，微粒自S/O/W乳液形成。微粒藉由過濾(5 μm)收集。用200 ml水將其洗滌5次且在20℃及0.030 mbar下乾燥36 h。將乾燥微粒篩過140 μm且在氮下填充於玻璃小瓶中。以彼方式來製備，微粒係藉由γ－輻射以30 kGy之劑量來滅菌。
微粒之粒度藉由雷射光繞射來量測。使用超音將微粒再懸浮於白色石油腦中。表2給出在120秒之超音處理後之直徑x90 (所有粒子之90%小於該值)。
微粒之檢定(活性成份之量)係在用超音將微粒溶於乙腈及甲醇之3：2混合物中且另外用乙酸鈉緩衝液(pH 4)1：1稀釋後，藉由HPLC來測定。藉由離心自剩餘顆粒物質清除溶液。
表2： 實例1－1至1－82：藉由一種PLGA製備之奧曲肽雙羥萘酸鹽微粒(參考實例)、兩種PLGA之摻合物及藉由僅具有一種PLGA之微粒批料所製備之微粒混合物。 A： 星形－PLG－D－葡萄糖50：50酯0.3 dL/g(%)B： PLGA 65：35酯0.6 dL/g(%)C： PLGA 75：25酯0.4 dL/g(%)D： PLGA 75：25酯0.6 dL/g(%)E： PLGA 85：15酯0.4 dL/g(%)F： PLGA 85：15酯0.6 dL/g(%)G： PLA 100：0酸0.2 dL/g(%)方法資訊＝其他方法資訊：7： 66 mM PBS pH 7.45： 69 mM檸檬酸鹽－磷酸鹽緩衝液pH 5.04： 69 mM檸檬酸鹽－磷酸鹽緩衝液pH 4.038： 渦輪機速度3800 rpm而不為4500 rpm1：25： 流速比率SO/W＝1：25而不為1：20GP： 齒輪泵而不為蠕動泵
實例2：媒劑組合物A至G
在用電磁攪拌器強烈攪拌下，將如給於表3中之量之CMC－Na、甘露醇及Pluronic F68溶於約90℃之溫度之約15 ml熱去離子水中。將所得澄清溶液冷卻至20℃且用去離子水填充至20.0 ml。
實例3：微粒懸浮液
於6 R小瓶中將170 mg之實例1－33之微粒懸浮於具有組合物D(表3)之1.0 ml媒劑中。藉由以手搖動約30秒將懸浮液均質化。可使用20量規針注射經復水之懸浮液而無任何問題。
實例4：冷凍乾燥微粒
將170 mg之實例1－33之微粒在1 ml之媒劑組合物F(表3)中復水，藉由攪拌1至12小時來均質化且隨後在冷凍乾燥器中冷凍乾燥。用1 ml純水(注射水(aqua ad injectabilia))復水經冷凍乾燥之微粒，產生快速及良好濕潤之微粒，其可使用20量規針來注射而無任何問題。
實例5：活體內(兔)之釋放概況
將含有奧曲肽之微粒懸浮於1 ml之適合水性媒劑中，較佳懸浮於媒劑D中，且以4 mg/kg之劑量，將所得懸浮液肌肉內(i.m.)注射於雄性紐西蘭白雜種兔(New Zealand White bastard rabbit)中。每一劑型(測試群)使用4隻動物。在所定義之時間後(表4中所指示)取出血漿樣本且分析奧曲肽濃度。

Claims (7)

  1. 一種呈微粒形式之持續釋放醫藥組合物，其包含作為活性成份之奧曲肽(octreotide)或其醫藥學上可接受之鹽及二或多種不同聚乳酸交酯-乙交酯共聚物(PLGAs)，其中該等PLGAs具有100：0至40：60之乳酸交酯：乙交酯單體比率，其中該等PLGAs之固有黏度為在氯仿中低於0.9dl/g，其中該等微粒具有自0.01微米至2mm之間的直徑，其中該等微粒係額外與抗聚結劑混合、經抗聚結劑覆蓋或經抗聚結劑塗佈，其中該等PLGAs係以聚合物摻合物之形式存在，及其中該等微粒係以單一組成物之形式存在。
  2. 如請求項1之醫藥組合物，其中該抗聚結劑為甘露醇。
  3. 如請求項1或2之醫藥組合物，其中至少兩種該等PLGAs為直鏈的。
  4. 如請求項1或2之醫藥組合物，其包含奧曲肽之雙羥萘酸鹽。
  5. 如請求項1或2之醫藥組合物，其係藉由γ輻射來滅菌。
  6. 一種製造如請求項1之微粒之方法，其包含(i)製備一內部有機相，其包含(ia)溶解該或該等聚合物於適合之有機溶劑或溶劑混合物中；(ib)溶解/懸浮/乳化該藥物物質於該步驟(ia)中獲得之聚合物溶液中；(ii)製備含有穩定劑之外部水相； (iii)混合該內部有機相與該外部水相以形成乳液；及(iv)藉由溶劑蒸發或溶劑萃取固化該等微粒，洗滌該等微粒，乾燥該等微粒，及將微粒篩過140μm。
  7. 一種投藥套組，其包含於小瓶中之如請求項1至5中任一項之醫藥組合物，及於安瓶、小瓶或預填充注射器中之水基媒劑或分離於雙腔室注射器中之微粒及媒劑。
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